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Mechanisms of Leptin
Action and Leptin
Resistance
Martin G. Myers,1 Michael A. Cowley,2
and Heike Münzberg1
1
Division of Metabolism, Endocrinology and Diabetes, Department of Medicine
and Department of Molecular and Integrative Physiology, University of Michigan
Medical School, Ann Arbor, Michigan 48109; email: [email protected],
[email protected]
2
Division of Neuroscience, National Primate Research Center, Oregon Health and
Sciences University, Beaverton, Oregon 97006; email: [email protected]
Annu. Rev. Physiol. 2008. 70:537–56
Key Words
First published online as a Review in Advance on
October 15, 2007
hypothalamus, VTA, obesity, diabetes
The Annual Review of Physiology is online at
http://physiol.annualreviews.org
This article’s doi:
10.1146/annurev.physiol.70.113006.100707
c 2008 by Annual Reviews.
Copyright All rights reserved
0066-4278/08/0315-0537$20.00
Abstract
The adipose tissue–derived hormone leptin acts via its receptor
(LRb) in the brain to regulate energy balance and neuroendocrine
function. LRb signaling via STAT3 and a number of other pathways
is required for the totality of leptin action. The failure of elevated
leptin levels to suppress feeding and mediate weight loss in common
forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation
of Tyr985 on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity.
Several unique features of the arcuate nucleus of the hypothalamus
may contribute to the severity of cellular leptin resistance in this
region. Other mechanisms that govern feeding behavior and food
reward may also underlie the inception of obesity.
537
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LEPTIN
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The adipose tissue–derived hormone leptin is
produced in proportion to fat stores. Circulating leptin serves to communicate the state of
body energy repletion to the central nervous
system (CNS) in order to suppress food intake
and permit energy expenditure (1–3). Many
of the physiological adaptations triggered by
prolonged fasting can be attenuated by exogenously administered leptin, which falsely signals to the brain that energy stores are replete
(3–5). Adequate leptin levels permit energy
expenditure on the processes of reproduction, tissue remodeling, and growth and similarly regulate the autonomic nervous system,
other elements of the endocrine system, and
the immune system (3–5). Conversely, lack
of leptin signaling due to mutation of leptin
(e.g., ob/ob mice) or the leptin receptor (LR)
(e.g., db/db mice) in rodents and humans results in increased food intake in combination with reduced energy expenditure and
a phenotype reminiscent of the neuroendocrine starvation response (including hypothyroidism, decreased growth, infertility,
and decreased immune function) in spite of
obesity (1, 2, 6, 7).
LEPTIN RECEPTORS AND SITES
OF LEPTIN ACTION
There are multiple LR isoforms, all of which
are products of a single Lepr gene (8, 9). The
Lepr gene contains 17 common exons and several alternatively spliced 3 exons. In mice, the
six distinct LR isoforms that have been identified are designated LRa–LRf. In all species,
LR isoforms are divisible into three classes:
secreted, short, and long. The secreted forms
are either products of alternatively spliced
mRNA species (e.g., murine LRe, which
contains only the first 14 exons of Lepr) or
proteolytic cleavage products of membranebound forms of LR. These secreted forms
contain only extracellular domains that bind
circulating leptin, perhaps regulating the
concentration of free leptin (10).
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Short-form LRs (LRa, LRc, LRd, and LRf
in mice) and the long-form LR (LRb in mice)
contain exons 1–17 of Lepr and therefore have
identical extracellular and transmembrane domains as well as the same first 29 intracellular amino acids but diverge in sequence
thereafter owing to the alternative splicing
of 3 exons. Short-form LRs contain exons
1–17 and terminate 3–11 amino acids after
the splice junction for total intracellular domain lengths of 32–40 amino acids. LRc-,
LRd-, and LRf-specific sequences are not well
conserved among species. However, LRa (the
most abundantly expressed isoform) is reasonably well conserved, as is LRb, which has
an intracellular domain of approximately 300
residues (8, 9).
LRb is crucial for leptin action. Indeed, the
originally described db/db mice lack LRb (but
not other LR forms) as a consequence of a
mutation that causes missplicing of the LRb
mRNA; these mice closely resemble db3J /db3J
mice (which are deficient in all LR isoforms)
and leptin-deficient ob/ob animals (3). The
function of short-form LRs is less clear, although proposed roles include the transport
of leptin across the blood-brain barrier (BBB)
and the production of circulating LR extracellular domain to complex with leptin (10, 11).
Many of the effects of leptin result from
actions in the CNS, particularly in the hypothalamus, a site of high LRb mRNA expression (12–15). In the hypothalamus, leptin acts
on neurons that directly or indirectly regulate
levels of circulating hormones (e.g., thyroid
hormone, sex steroids, and growth hormone)
(12, 16, 17). Leptin action on these hypothalamic neurons also regulates the activity of the
autonomic nervous system, although direct
effects of leptin on LRb-containing neurons
in the brainstem and elsewhere probably also
have an important role (18). The effects of leptin on the immune system and vasculature appear to result from direct action on hematogenous cells that contain LRb (5, 19). Leptin
may also regulate glucose homeostasis independently of its effects on adiposity; leptin
regulates glycemia at least partly via the CNS,
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but it may also directly regulate pancreatic βcells and insulin-sensitive tissues (20–24).
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LEPTIN REGULATION OF
NEURAL NETWORKS AND
NEUROPHYSIOLOGY
LRb is present in several tissues; the highest
levels are in neurons of several nuclei of the
hypothalamus, including the arcuate (ARC),
dorsomedial (DMH), ventromedial (VMH),
lateral hypothalamic area (LHA), and ventral premammillary (PMv) nuclei (12–14, 25).
Other sites within the brain that have been
shown to express functional LRb include the
ventral tegmental area (VTA), brainstem [including the nucleus of the solitary tract (NTS)
and dorsal motor nucleus of the vagus], and
the periaqueductal gray matter, among others.
LRb action on two populations of ARC
neurons is particularly well characterized.
One population synthesizes neuropeptide Y
(NPY) and agouti-related peptide (AgRP),
and the other synthesizes pro-opiomelanocortin (POMC) (12, 15). POMC is processed to produce α-melanocyte-stimulating
hormone (αMSH) in LRb/POMC neurons;
αMSH signals anorexia (decreased appetite)
by activating the melanocortin-4 receptor
(MC4R) and the melanocortin-3 receptor
(MC3R) (26–31). LRb stimulates the synthesis of POMC, activates LRb/POMC
neurons (15, 32), and stimulates αMSH secretion (33). NPY is an orexigenic (appetitestimulating) hormone that also suppresses
the central LRb-mediated growth and reproductive axes (34–37). AgRP is an antagonist of αMSH/MC4R signaling as well as
an inhibitor (inverse agonist) of endogenous
MC4R activity (36, 38). Leptin acts via LRb to
inhibit NPY/AgRP neurons and suppress the
expression and secretion of NPY and AgRP
(15, 32, 33). Thus, LRb signaling stimulates
the production and secretion of anorectic neuropeptides and reciprocally suppresses levels
of orexigenic peptides. Conversely, a decrease
or deficiency in leptin action (e.g., during starvation or in ob/ob and db/db mice) stimulates
appetite by the suppression of the synthesis
of anorectic neuropeptides (e.g., POMC) and
increased expression of orexigenic peptides
(e.g., NPY and AgRP).
Although we now know a great deal
about the mechanisms by which the ARC
NPY/AgRP and POMC neurons function,
numerous questions remain regarding the
contributions of each circuit to the regulation of feeding in general and in response
to leptin under physiological conditions. Although ablation of AgRP neurons results in
hypophagia and ablation of POMC or central
melanocortin receptors results in severe obesity (27, 39), deletion of LRb from POMC
neurons or the restoration of LRb in the
ARC of db/db animals results in only modest alterations in body weight (although these
manipulations robustly modulate glucose
homeostasis) (40, 41).
Furthermore, although interference with
LRb → STAT3 (signal transducer and activator of transcription 3) signaling results
in dramatic hyperphagia and obesity, deletion of STAT3 in ARC neurons only modestly impacts body energy homeostasis (42–
44). Thus, although melanocortins and ARC
neurons generally effect powerful appetitive
signals, they may not constitute the majority of the leptin-mediated anorectic signal;
the aggregate leptin signal is likely mediated
in concert with many other populations of
LRb-expressing neurons that require further
analysis. Indeed, ARC LRb neurons comprise
only 15–20% of the total number of LRbexpressing neurons within the CNS (25), and
other populations of LRb neurons, including those in the VMH and VTA, clearly mediate important components of leptin action
(45–47).
LEPTIN RECEPTOR SIGNALING
LRb belongs to the interleukin (IL)-6 receptor family of class 1 cytokine receptors, which
contain an extracellular ligand-binding domain, a single transmembrane domain, and
a cytoplasmic signaling domain (8, 48). Like
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other cytokine receptors, LRb does not contain intrinsic enzymatic activity but instead
signals via a noncovalently associated tyrosine kinase of the Jak kinase family ( Jak2
in the case of LRb) (49–51). Leptin binding alters the conformation of the preformed
LRb homodimer, enabling transphosphorylation and activation of the intracellular LRbassociated Jak2 (8, 52, 53). The activated Jak2
molecule then phosphorylates other tyrosine
residues within the LRb/Jak2 complex to mediate downstream signaling (54, 55).
Signaling by cytokine receptors requires
a proline-rich Box 1 motif critical for Jak
kinase interaction and activation; additional,
less-conserved sequences COOH-terminal to
Box 1 (sometimes referred to as Box 2) are
also important for Jak interactions and likely
function in Jak isoform selectivity (48, 49,
51, 56). In the case of LRb, intracellular
residues 31–36 (i.e., those immediately downstream of the alternative splice junction following amino acid 29) compose Box 2 and
dictate Jak2 selectivity (51, 56). This Box 2
sequence is absent from all described short
LR isoforms—consistent with the inability of
these molecules to mediate leptin action in
db/db animals (8, 51, 54).
Tyrosine kinase–dependent signaling generally proceeds via the phosphotyrosinemediated recruitment of signaling proteins
that contain specialized phosphotyrosinebinding domains (e.g., SH2 domains) (57).
Each SH2 domain isoform recognizes phosphotyrosine in a specific amino acid context. Thus, although tyrosine phosphorylation acts as a molecular switch to recruit
SH2-containing proteins, each tyrosine phosphorylation site recruits only specific SH2
isoforms because each isoform recognizes
specific surrounding amino acids as well as the
phosphotyrosine residue. For instance, the
SH2 domain of the latent transcription factor STAT3 binds to phosphotyrosine in the
context of a Y(P)XXQ motif (58, 59).
Understanding signaling by the LRb/Jak2
complex thus requires defining the tyrosine
phosphorylation sites on LRb and Jak2 and
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the SH2 proteins that they recruit. There are
three conserved residues on the intracellular
domain of LRb: Tyr985 , Tyr1077 , and Tyr1138 .
Data from our and other labs suggest that all
three of these sites are phosphorylated and
contribute to downstream leptin signaling (8,
54, 55, 60, 60a).
There are thus four tyrosine phosphorylation signaling pathways that can derive from
LRb (Figure 1): those originating directly
from Jak2 tyrosine phosphorylation sites and
those emanating from the phosphorylation of
Tyr985 , Tyr1077 , and Tyr1138 of LRb. The phosphorylation of Tyr985 creates a binding site for
the COOH-terminal SH2 domain of the tyrosine phosphatase SHP-2, leading to the activation of the canonical p21ras → ERK signaling pathway in cultured cells (51, 55, 61).
Phosphorylation of Tyr1138 recruits
STAT3 to the LRb/Jak2 complex, resulting
in the tyrosine phosphorylation and subsequent nuclear translocation of STAT3 to
mediate transcriptional regulation (54, 55).
Among the STAT3-regulated genes is the
SH2 domain–containing feedback inhibitor
SOCS3 (suppressor of cytokine signaling 3)
(55, 62). Following its STAT3-dependent
production during leptin stimulation, SOCS3
binds to Tyr985 of LRb to mediate the inhibition of LRb → STAT3 signaling (63);
SOCS3 also binds to a separate site on Jak2
(64, 65).
Tyr1077 mediates a crucial component of
STAT5 (signal transducer and activator of
transcription 5) phosphorylation and transcriptional regulation by leptin, although
Tyr1138 also contributes to STAT5 activation
(60, 60a). Tyr1077 does not regulate STAT3
signaling, although it may promote the increased phosphorylation of LRb Tyr985 .
Jak2 tyrosine phosphorylation during LRb
stimulation may mediate some signals independently of tyrosine phosphorylation sites
on LRb (55). The individual phosphorylation
sites on Jak2 are beginning to be enumerated (66–73). Unfortunately, many more remain to be identified, and the binding partners and signals mediated by many sites are
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Figure 1
LRb signaling, feedback inhibition, and the regulation of physiology. Leptin binding to the extracellular
domain of LRb, the functional leptin receptor isoform, mediates the activation of the intracellular,
LRb-associated Jak2 tyrosine kinase, resulting in Jak2 autophosphorylation on tyrosine residues (pY) as
well as the phosphorylation of three tyrosine residues on the intracellular tail of LRb: Y985 , Y1077 , and
Y1138 . pY1138 recruits signal transducer and activator of transcription (STAT) 3, which is activated to
mediate transcriptional events, including the transcription of pro-opiomelanocortin (POMC) and the
inhibitory suppressor of cytokine signaling 3 (SOCS3) protein. pY1077 recruits and mediates the
transcriptional activation of STAT5. pY985 recruits the tyrosine phosphatase SHP-2 and also binds to
SOCS3 and mediates feedback inhibition of LRb signaling (dotted lines). The tyrosine phosphatase
PTP1B, although not regulated by leptin in this manner, also inhibits LRb/Jak2 signaling. The cellular
mechanisms by which LRb couples to the regulation of phosphatidylinositol 3-kinase (PI3K),
mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK) pathways remain
unclear. Y1138 -mediated STAT3 signaling by LRb (presumably via POMC and additional mechanisms) is
crucial to the regulation of anorexia and energy expenditure by leptin. Although Y985 clearly functions to
attenuate LRb signaling in vivo, a role for Y985 and SHP-2 in promoting leptin action has not been
defined. Leptin mediates permissive effects upon reproduction, growth, hematopoietic effects (e.g.,
immune and platelet function), and the inhibition of agouti-related protein (AgRP)/neuropeptide Y
(NPY) neurons of Y1138 and Y985 , perhaps via pY sites on Jak2 or via pY1077 .
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LRb SIGNALING VIA STAT3
MEDIATES A SUBSET OF
LEPTIN ACTIONS
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not known, limiting our understanding of the
mechanisms by which Jak2-dependent signals are mediated. LRb stimulation mediates
the tyrosine phosphorylation of IRS proteins
and regulates the PI 3 -kinase pathway (74–
76) as well as the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways (77, 78), although
the molecular mechanisms by which LRb regulates these pathways remain unclear.
Thus far, roles for two signals mediated
by LRb tyrosine phosphorylation sites—the
Tyr1138 → STAT3 pathway and the Tyr985 →
SOCS3/SHP2 pathway—have been examined in leptin action in vivo (Figure 2).
We have directly addressed the contribution
of the LRb-STAT3 pathway to physiology
Striatum
amygdala
PVH
LHA
DMH
POA
VMH
PMv
ARC
VTA
PAG
Target areas to which LRb neurons project
(contain few or no LRb neurons)
Areas where little is known about the
projections of the LRb-expressing neurons
DR
PB
NTS
Components and regulators of the
mesolimbic dopamine system
Figure 2
A distributed network of LRb-expressing neurons in the CNS regulates multiple neural processes.
Shown in blue, yellow, and brown bubbles are brain regions containing significant populations of
LRb-expressing neurons. Yellow bubbles indicate areas where little is known about the projections of the
LRb-expressing neurons. Bubbles with arrows have LRb neurons with somewhat defined projection
patterns. Target areas to which LRb neurons project but that contain few or no LRb neurons are denoted
as light green bubbles. Components and regulators of the mesolimbic dopamine system are shown in
brown bubbles. ARC, arcuate nucleus; PVH, paraventricular hypothalamic nucleus; VMH, ventromedial
hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamic area; PMv,
ventral premammilary nucleus; POA, preoptic area; VTA, ventral tegmental area; PAG, periaqueductal
gray; DR, dorsal raphe; PB, parabrachial nucleus; NTS, nucleus of the solitary tract.
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by studying homologously targeted knock-in
mice in which LRb is replaced by a mutant
molecule (LRbS1138 ) that contains a substitution mutation of Tyr1138 (the STAT3 binding
site) (42). Although LRbS1138 fails to mediate STAT3 activation during leptin signaling,
this mutant regulates all other known LRb
signaling pathways. The use of the knockin approach ensures that the expression pattern and levels of LRbS1138 mirror those of
wild-type LRb.
Similar to db/db animals, mice homozygous
for LRbS1138 expression (s/s) display hyperphagia and decreased energy expenditure, resulting in profound obesity in the face of dramatically increased serum leptin levels. The high
circulating leptin levels in s/s animals not only
correlate with increased adipose mass in these
mice but also indicate resistance to the energy homeostatic effects of leptin (42). Feeding is similarly high in s/s and db/db mice, and
thyroid function and energy expenditure are
similarly decreased in these two mouse strains
(79).
Important differences exist between the
phenotypes of s/s mice (missing only the LRbSTAT3 signal) and db/db mice (devoid of all
leptin signals), however (42). Whereas db/db
animals are floridly diabetic and infertile and
demonstrate decreased linear growth, s/s mice
demonstrate greatly improved glucose tolerance compared with db/db mice. The s/s mice
also retain fertility and demonstrate increased
linear growth as well as immune and vascular
reactivity to leptin compared with wild-type
animals (42, 79–83).
Analysis of hypothalamic neuropeptide expression reveals that, similar to db/db mice, s/s
mice have decreased POMC mRNA levels in
the hypothalamus (42). By contrast, whereas
db/db animals display dramatic induction of
hypothalamic NPY mRNA, levels of NPY
message are near normal in s/s animals. Furthermore, the activity of these AgRP/NPY
neurons is appropriately suppressed in s/s, but
not db/db, animals (84). These data suggest
that LRb-STAT3 signaling is a crucial regulator of hypothalamic melanocortin action
and that dysregulated melanocortin signaling (as opposed to alterations in NPY) may
contribute to the obesity of s/s animals, although STAT3 presumably mediates other
leptin effects in other LRb-expressing neurons. Hence, non-STAT3 LRb signals are
critical regulators of neural activity and NPY
expression in the LRb/NPY neuron.
Clearly, pathways independent of LRb →
STAT3 regulate glycemic control, the function of hematopoietic and vascular cells, reproduction, growth, and NPY/AgRP neurons
in response to leptin. The phenotype of the
s/s animals does not suggest the irrelevance of
non-STAT3 pathways in other aspects of energy balance, however, and reveals only that
STAT3 signaling is important for the regulation of energy homeostasis. Thus, signals
independent of Tyr1138 → STAT3 may contribute to energy balance as well as to the
myriad leptin effects that are preserved in
s/s mice.
LRb Tyr985 ATTENUATES
LEPTIN ACTION IN VIVO
To understand the contribution of LRb Tyr985
to leptin action and inhibition in vivo, we generated mice in which LRb was homologously
replaced by a mutant containing a substitution of Tyr985 that abrogates phosphorylation
of the site and blocks SHP-2/SOCS3 recruitment (55, 61, 63, 85). Mutation of Tyr985 in
vivo results in reduced feeding and adiposity,
decreased orexigenic ARC neuropeptide expression, and increased baseline STAT3 activation in female l/l mice—all in the face of low
leptin levels. Coupled with the increased sensitivity of l/l animals to exogenous leptin, these
observations suggest that mutation of Tyr985
blocks the activation of an inhibitory Tyr985 dependent LRb signal, ultimately leading to
increased leptin sensitivity in vivo. These results suggest an important role for Tyr985 in
the attenuation of leptin action in vivo, consistent with results from cultured cells suggesting an important role for Tyr985 in the inhibition of LRb signaling (63, 86, 87).
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Leptin resistance:
the failure of high
levels of leptin in
obese individuals to
suppress feeding and
prevent or mitigate
obesity
17:52
Because Tyr985 of LRb recruits both
SHP-2 and SOCS3 (63, 87, 88), the failure
of LRbL985 to recruit either of these proteins
may theoretically underlie the lean, leptinsensitive phenotype of l/l mice. Many data
from cultured cells and animals support a
primary role for SOCS3 in the inhibition
of LRb signaling, however, suggesting that
SOCS3 (rather than SHP-2) mediates Tyr985 dependent inhibition of LRb (61–63, 83,
89–91).
The phenotype of l/l mice also suggests
that SHP-2 may not be required for the regulation of growth or reproduction by leptin
and does not mediate essential anorectic signals. This finding contrasts with the obesity
and impaired neuroendocrine function in animals with deletion of SHP-2 in the forebrain
(91), consistent with the notion that disruption of SHP-2 alters signaling by numerous
factors other than leptin and in a wide variety of neuronal populations (92, 93). The
loss of SHP-2 recruitment by leptin in l/l animals may result in a diminution of anorectic function that is obscured by the enhancement of overall LRb signaling owing to the
concomitant loss of inhibitory signals, however. Collectively, these findings suggest that
LRb Tyr1138 - and Tyr985 -independent signals
likely contribute to the regulation of growth,
reproduction, and glucose homeostasis by leptin (42). These signals may include the LRb
Tyr1077 /STAT5 pathway or signals mediated
by the LRb-associated Jak2 independently of
LRb tyrosine phosphorylation (3, 60, 74). Additionally, some possible downstream pathways include the PI 3 -kinase, mTOR, and
AMPK pathways, although we cannot rule out
the possibility that other uncharacterized signals may also participate.
LEPTIN RESISTANCE IN
OBESITY
An absolute deficit of leptin does not underlie most cases of obesity: Indeed, most obese
individuals exhibit elevated circulating leptin
levels commensurate with their adipose mass
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(94–96). The apparent conundrum that this
observation implies (why do elevated leptin
levels not act to decrease feeding and thus
prevent obesity?) has given rise to the notion of the existence of physiological leptin
resistance. Simply put, the failure of high levels of leptin to suppress feeding and decrease
body weight/adiposity to prevent or mitigate
obesity suggests a relative resistance to the
catabolic effects of leptin action in obesity.
A number of mechanisms have been proposed to explain leptin resistance; these include alterations in the transport of leptin
across the BBB, alterations in cellular LRb signaling, perturbations in developmental programming, and others (97–99; 101). Indeed,
each of these mechanisms may contribute to
the totality of leptin resistance. Although the
absolute lack or genetic alteration of LRb
does not underlie most leptin resistance (95,
100), the preponderance of data confirm that
alterations in cellular LRb signaling, especially in the ARC, play a crucial role in leptin
resistance (98, 101, 102).
LRb SIGNAL ATTENUATION
AND EVIDENCE FOR CELLULAR
LEPTIN RESISTANCE
IN OBESITY
The concept of leptin resistance is analogous
to the syndrome of insulin resistance, in which
elevated levels of insulin are required to mediate adequate glucose disposal and metabolic
control. In the case of insulin resistance, a
number of intracellular pathways contribute
to the attenuation of insulin signaling in
insulin-responsive tissues such as muscle and
liver (103). Indeed, diet-induced obese (DIO)
animals (in which consumption of a palatable,
calorically dense diet promotes obesity) are
leptin resistant, displaying decreased anorectic response and decreased amplitude of maximal LRb signaling in the hypothalamus in
response to high-dose leptin treatment, as evidenced by decreased STAT3 phosphorylation
and neuropeptide release compared with controls (33, 98, 101, 102). Furthermore, maximal
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leptin-stimulated neuropeptide release is impaired in explanted tissues from DIO mice,
demonstrating the preservation of impaired
leptin signaling outside of the physiological
milieu of DIO mice (33).
Others and we have therefore undertaken
to define the cellular mechanisms that contribute to the attenuation of LRb signaling,
with the idea that these mechanisms may contribute to a cellular leptin resistance similar
to the insulin signaling defects in insulin resistance (98). As noted above, SOCS3 binds
to LRb Tyr985 and Jak2 to impair LRb signaling in cultured cells (63). Additionally, in
mice, decreasing SOCS3 expression in the
whole body or deleting SOCS3 in neurons
increases the amplitude of LRb signaling, resulting in animals that are leaner than wild
types at baseline and that are resistant to DIO
(90, 104). As detailed above, LRb Tyr985 also
mediates the attenuation of LRb signaling in
cultured cells, and mutation of this residue
in l/l mice results in augmented leptin sensitivity, leanness, and resistance to DIO (63,
85, 87, 88). Thus, Tyr985 and SOCS3 attenuate LRb signaling and contribute to leptin
resistance.
The tyrosine phosphatase PTP1B dephosphorylates Jak2 to diminish LRb signaling in
cultured cells, and whole-body or neuronspecific deletion of PTP1B increases leanness and leptin sensitivity (105–107). Neural
PTP1B expression or activity is not altered
by leptin or adiposity, however, suggesting
that, although PTP1B physiologically attenuates leptin action and thus may represent an
important therapeutic target, it may not underlie altered leptin signaling in obesity. Indeed, although neuronal deletion of PTP1B
renders animals lean and leptin sensitive, the
effect of PTP1B on adiposity is independent
of DIO (that is, the increased leanness of neuronal PTP1B knockout mice relative to controls does not differ by diet) (105).
Leptin (which is increased in obesity) itself
stimulates the phosphorylation of LRb Tyr985
to limit LRb signaling (63, 85, 87, 88), and
SOCS3 expression increases in response to
leptin and is elevated in the hypothalami of
obese animals (62, 102, 108, 109). In addition
to leptin, other cytokines promote SOCS3 accumulation. Thus, increased activity in any of
these metabolic and inflammatory pathways
has the potential to impair LRb signaling, and
the convergence of all these signaling systems
upon SOCS3 mirrors some of the phenotypes
that comprise the metabolic syndrome. Thus,
Tyr985 and SOCS3 contribute to cellular leptin resistance, specifically in states of obesity,
and leptin/obesity activate these feedback signals to attenuate LRb signaling at high leptin levels, as found in obesity. This is not
to say that increased leptin and/or obesity
block LRb signaling to such an extent that
LRb activity at these elevated circulating levels falls below that observed in lean controls
with lower leptin levels, however. Rather, each
increase in circulating leptin levels yields a
smaller and smaller increase in LRb signaling
over the baseline observed at low leptin levels
(Figure 3). Indeed, DIO mice with severalfold increases in circulating leptin levels
demonstrate only slightly increased baseline
LRb signaling compared with normal, chowfed mice (but this would presumably support
some continued increase in Tyr985 phosphorylation and SOCS3 expression) (85). Thus,
baseline LRb signaling in DIO mice, although
modestly increased, is not proportional to
their degree of hyperleptinemia. This LRb
signal attenuation is also evident by the substantially reduced response to acute high-dose
leptin administration (33, 85, 101).
THE ARCUATE NUCLEUS AS A
CRUCIAL SITE OF CELLULAR
LEPTIN RESISTANCE
The cellular leptin resistance phenotype of
DIO animals is most prominently detected
in the ARC relative to other hypothalamic
sites (33, 102). Furthermore, the increased
expression of SOCS3 in seasonally obese rodents is localized to the ARC (108, 109). This
ARC specificity of cellular leptin resistance
and increased SOCS3 expression raises the
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question of how the ARC differs from other
hypothalamic sites. Potentially increased access of leptin and other factors from the
circulation into the ARC relative to other
hypothalamic sites (where leptin access is limited by transport mechanisms across the BBB)
may represent one such mechanism. Indeed,
this notion finds support in our recent data
demonstrating that endogenous circulating
leptin (in untreated, ad libitum–fed mice) promotes increased LRb signaling in ARC neurons compared with LRb neurons in other
sites (109a). Indeed, the time course of LRb
signaling is delayed in non-ARC neurons rela-
Leptin action
a
No F-Inh
Adequate:
normal
neuroendocrine
function
F-Inh
Inadequate: reduced
neuroendocrine function
Underweight
Normal
Overweight
Obese
[Leptin]
b Hypothetical AgRP neuron
Membrane potential
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Loss of ghrelin’s
ability to initiate AP
Ghrelin
AP threshold
F-Inh
No F-Inh
Overweight
Normal
Obese
[Leptin]
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Max
tive to ARC neurons in response to peripheral
leptin administration but is similar between
hypothalamic sites after central leptin administration (which circumvents the BBB) (109a).
This result is consistent with differential access of the ARC LRb neurons to circulating
leptin (as opposed to intrinsic differences in
the leptin responsiveness of the LRb neurons
among sites).
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 3
Theoretical functional consequences of the
attenuation of leptin action in obesity. (a) Shown is
a theoretical graph of how leptin action on body
weight (e.g., via STAT3 phosphorylation) and on
the reproductive axis (via an unknown signaling
pathway) varies with leptin concentration in the
presence or absence of feedback inhibition (F-Inh)
mechanisms that attenuate leptin action in
proportion to leptin levels and/or adiposity. At low
leptin levels, at which the effect of F-Inh is
minimal, the curves for F-Inh and no F-Inh
overlie. The lines diverge as leptin and F-Inh
increase. With increasing concentrations of
endogenous circulating leptin in the case of F-Inh,
leptin action increases modestly. The amplitude of
the leptin signal in response to a single large dose
of leptin (seen at max) is attenuated in animals with
increased baseline leptin levels (at which F-Inh
levels are high before the leptin dose is given)
compared with animals with low baseline levels of
leptin and low F-Inh; the latter group of animals
should demonstrate a response analogous to the
maximum of the no F-Inh line. (b) Mechanism by
which the presence of F-Inh enables the detection
of energy flux via hormones such as ghrelin in the
face of high leptin levels. Taken is the hypothetical
case for a leptin-inhibited, ghrelin-activated
agouti-related protein (AgRP) neuron. Curves for
the effect of leptin on the membrane potential are
shown for various leptin levels for the cases of no
F-Inh (dark blue) and F-Inh (blue). Also shown is
the effect for this theoretical neuron of a high
physiological dose of ghrelin, which relatively
depolarizes the neuron ( gray arrow) and shifts the
leptin curves (red ) as shown. When there is no
F-Inh, ghrelin is incapable of depolarizing the
theoretical neuron to the point of action potential
(AP) generation (AP threshold) at high levels of
leptin, whereas the attenuation of leptin action by
F-Inh mechanisms at chronically high leptin levels
permits the detection of ghrelin/energy flux even
in the face of high leptin levels.
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Furthermore, peripheral application of the
BBB-impermeant retrograde neuronal tracer
fluorogold reveals a substantial population of
highly leptin-sensitive LRb neurons that directly contact the circulation in the ARC, but
not elsewhere in the hypothalamus (109a).
Hence, a population of ARC LRb neurons
is directly exposed to circulating leptin levels
and poised to respond more sensitively to circulating leptin (and other factors) compared
with LRb neurons at other sites. These ARC
LRb neurons may be more prone to the development of cellular leptin resistance than other
LRb neurons owing to their increased exposure to high leptin levels or to other potential
circulating mediators of cellular leptin resistance in obesity.
WHEREFORE CELLULAR
LEPTIN RESISTANCE?
We are faced with the challenge of explaining the need for and the physiological
consequences of feedback mechanisms that
limit LRb signaling in hyperleptinemic/obese
states. For some organisms, such as seasonal
mammals, there is a periodic need to increase
energy stores, and thus these feedback mechanisms may work in concert with other processes that increase energy intake to promote
seasonal energy storage. For nonseasonal animals, such as humans, another potential explanation for feedback inhibition of LRb signaling arises from the need to sense not only the
content of body energy stores but also the flux
of energy, as detailed for the case of reproduction in On Fertile Ground: A Natural History of
Reproduction (109b). Even when energy stores
are relatively high (resulting in high circulating leptin levels), it is important to evaluate
the rate of energy expenditure (energy flux)
to determine if the organism is in a positive or
a negative energy balance and thus enable the
organism to further increase or maintain food
consumption despite already elevated energy
stores. Specific instances in which expenditure may be high and caloric intake must be
increased (even in the face of normal energy
stores) include pregnancy, lactation, and intensive exercise. Indicators of high energy flux
that must be sensed even if circulating levels
indicate significant energy stores include falls
in leptin levels (even within the high end of
the normal physiological range) as well as opposing and short-term acting factors like the
gut hormone ghrelin. However, in a system in
which increases in circulating leptin levels linearly amplify LRb signaling (leptin rises and
falls in direct proportion to energy stores at
all levels of adiposity), it is difficult to detect
alterations in energy flux at high leptin levels because very elevated LRb signaling could
overwhelm opposing signals like ghrelin
(Figure 3). In contrast, the presence of a
leptin-stimulated feedback mechanism prevents unlimited leptin action during hyperleptinemia. Thus, this system protects the
ability to detect alterations in energy flux by
ensuring that signals like ghrelin are not overwhelmed at relatively high leptin levels if negative energy balance exists.
In addition to mediators of cellular leptin
resistance, such as Tyr985 and SOCS3, other
mechanisms of cellular leptin resistance and
any mechanism of leptin resistance that is increased by adiposity or leptin levels (including
alterations in BBB leptin transport) should act
in this manner.
OTHER POTENTIAL
MECHANISMS OF LEPTIN
RESISTANCE
Although cellular leptin resistance is physiologically relevant and even desirable to permit
the detection of energy flux in states in which
increased adipose stores exist, such mechanisms that require leptin or increased adiposity to initiate leptin resistance cannot underlie
the inception of obesity but can only contribute to its stability. For example, mice that
are put on a high-fat diet to induce DIO begin with a perfectly acting LRb signaling system. The diet, rather than alteration of the
LRb system itself, must trigger the increased
energy intake, although the developing
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feedback inhibition/cellular leptin resistance
exacerbate and stabilize the ensuing increase
in body weight. Although genetic variability in factors that attenuate LRb signaling
(e.g., PTP1B, SOCS3) may underlie a cellular leptin resistance that causes obesity, there
is clearly a strong environmental component
to obesity, as evidenced by the rapidly increasing rates of obesity in industrialized countries
today. Some evidence exists for developmental alterations in neural and other systems that
may underlie some propensity to obesity, but
the ready availability of palatable, calorically
dense food (the basis for DIO in experimental animals) clearly plays a dominant role. Indeed, the obesity and cellular leptin resistance
of DIO animals are reversed by replacing the
palatable calorie-dense chow used to promote
obesity with standard chow (33).
Although some of the obesogenic effects
of tasty foods may be due to their nutrient
content, the hedonic or rewarding properties of these foods also contribute (110, 111).
Leptin regulates the perception of the rewarding value of palatable food (as well as that of
other addictive substances, such as drugs of
abuse) (112–115).
Leptin regulates a broadly distributed network of LRb-expressing neurons in the brain
to orchestrate an array of neural processes
(Figure 2). Some of the neural mechanisms by
which leptin may control food reward are beginning to be elucidated via the investigation
of the interaction of leptin with the mesolimbic dopamine (DA) system. The core of the
mesolimbic DA system lies in a set of DA neurons in the ventral tegmental area that project
forward to innervate the striatum (nucleus accumbens, caudate/putamen), amygdala, and
prefrontal cortex (111). It is by acting upon
this system that drugs of abuse generally exert their reinforcing effects, and the activity
of this system is clearly important to mediate the incentive salience of food and other
natural rewards. Although ARC LRb neurons
do not project to the VTA and there is little
evidence for the modulation of the mesolimbic circuitry by NPY or melanocortin action,
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a number of research groups have demonstrated the presence of LRb-expressing VTA
DA neurons and proven the ability of leptin to alter the physiology of this system (45,
47, 116, 117). Additionally, feeding and leptin
modulate the reward associated with intracranial self-stimulation specifically in the LHA,
which is mediated by the mesolimbic reward
circuitry (116, 118). Indeed, we have identified a novel population of LRb-expressing
neurons in the LHA that project to the VTA
to regulate the mesolimbic DA system. Thus,
leptin acts via multiple ARC-independent systems to control the VTA and the mesolimbic
DA system at its inception in the VTA, and
these sites of leptin action likely regulate the
incentive salience of food.
How then is the action of leptin to regulate
the perception of food reward overwhelmed
to promote obesity in the face of plentiful
tasty food? Leptin is only one of many inputs into the mesolimbic DA system and other
neural pathways that regulate the perception
of food reward, and physiological leptin levels may not be able to suppress the myriad
other signals that compel us to consume tasty
food. Although leptin may reasonably inhibit
the drive to overeat foods with only modestly
rewarding properties, leptin may be insufficient to effectively compete with the rewarding properties of more palatable treats because
these more-rewarding foods engage powerful
neural responses that oppose leptin within the
mesolimbic DA system and elsewhere.
Indeed, endogenous (and exogenous)
cannabinoids modulate the mesolimbic DA
system and exert powerful anorectic signals.
The finding that inhibitors of endocannabinoid action promote weight loss speaks to the
importance of this system in energy balance
(119). Furthermore, although leptin regulates
the production of endogenous cannabinoids
to some extent, many other factors, including
stress, also contribute to their regulation.
Where does this leave us in terms of leptin resistance, cellular leptin resistance, the
problem of plentiful calorie-dense foods, and
therapeutic alternatives? First, many lines of
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evidence suggest that, even if cellular leptin
resistance or other obesity-induced mechanisms of leptin resistance may not be the initiating insult in obesity, it clearly contributes
to the ability to become and remain obese,
and the blockade of processes that mediate
leptin signal attenuation remains an attractive
potential therapeutic modality. Furthermore,
the investigation of the leptin signaling system has led us to a more detailed and general
understanding of the regulatory mechanisms
of food intake, including the melanocortin
or the mesolimbic VTA/DA system, that can
be considered general tools in the regulation of feeding that are employed by several
peptides (e.g., leptin, ghrelin, serotonin, neurotensin, etc.). A more detailed understanding of the widely distributed network of LRb
neurons in several poorly investigated CNS
sites and the neural mechanisms by which
leptin and other cues (nutritional, taste, etc.)
regulate the perception of food reward will
likely reveal additional potential therapeutic
targets.
DISCLOSURE STATEMENT
M.G.M. and H.M. are not aware of any biases that might be perceived as affecting the objectivity
of this review.
M.A.C. is Chief Scientific Officer of, and owns stock in, Orexigen Therapeutics, Inc.,
a company that is developing pharmaceutical approaches to treat obesity and is developing
combination therapies that attempt to bypass leptin resistance. The work described in this
manuscript was not supported by Orexigen Therapeutics. Oregon Health and Sciences University (OHSU) and M.A.C. have a significant financial interest in Orexigen Therapeutics,
which may have a commercial interest in the results of this research and technology; this potential conflict has been reviewed and managed by the OHSU Conflict of Interest in Research
Committee and the Integrity Program Oversight Council.
In the past M.A.C. has received grant support from the NIH (RR 0163, DK 62202), Oregon
National Primate Research Center, and Orexigen Therapeutics. In the past M.A.C. has received compensation from Orexigen Therapeutics, Novo Nordisk, Merck & Co., Semaphore
Pharmaceuticals, Konovo Inc., 7TM Pharma, Ipsen, and Amylin Pharmaceuticals.
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Contents
Volume 70, 2008
Frontispiece
Joseph F. Hoffman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p xvi
PERSPECTIVES, David Julius, Editor
My Passion and Passages with Red Blood Cells
Joseph F. Hoffman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor
Calcium Cycling and Signaling in Cardiac Myocytes
Donald M. Bers p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 23
Hypoxia-Induced Signaling in the Cardiovascular System
M. Celeste Simon, Liping Liu, Bryan C. Barnhart, and Regina M. Young p p p p p p p p p p p 51
CELL PHYSIOLOGY, David E. Clapham, Associate and Section Editor
Bcl-2 Protein Family Members: Versatile Regulators of Calcium
Signaling in Cell Survival and Apoptosis
Yiping Rong and Clark W. Distelhorst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 73
Mechanisms of Sperm Chemotaxis
U. Benjamin Kaupp, Nachiket D. Kashikar, and Ingo Weyand p p p p p p p p p p p p p p p p p p p p p p p p 93
ECOLOGICAL, EVOLUTIONARY, AND COMPARATIVE
PHYSIOLOGY, Martin E. Feder, Section Editor
Advances in Biological Structure, Function, and Physiology Using
Synchrotron X-Ray Imaging
Mark W. Westneat, John J. Socha, and Wah-Keat Lee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p119
Advances in Comparative Physiology from High-Speed Imaging
of Animal and Fluid Motion
George V. Lauder and Peter G.A. Madden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p143
vii
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ENDOCRINOLOGY, Holly A. Ingraham, Section Editor
Estrogen Signaling through the Transmembrane G Protein–Coupled
Receptor GPR30
Eric R. Prossnitz, Jeffrey B. Arterburn, Harriet O. Smith, Tudor I. Oprea,
Larry A. Sklar, and Helen J. Hathaway p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p165
Insulin-Like Signaling, Nutrient Homeostasis, and Life Span
Akiko Taguchi and Morris F. White p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p191
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The Role of Kisspeptins and GPR54 in the Neuroendocrine
Regulation of Reproduction
Simina M. Popa, Donald K. Clifton, and Robert A. Steiner p p p p p p p p p p p p p p p p p p p p p p p p p p p213
GASTROINTESTINAL PHYSIOLOGY, James M. Anderson, Section Editor
Gastrointestinal Satiety Signals
Owais B. Chaudhri, Victoria Salem, Kevin G. Murphy, and Stephen R. Bloom p p p p p239
Mechanisms and Regulation of Epithelial Ca2+ Absorption in Health
and Disease
Yoshiro Suzuki, Christopher P. Landowski, and Matthias A. Hediger p p p p p p p p p p p p p p p p257
Polarized Calcium Signaling in Exocrine Gland Cells
Ole H. Petersen and Alexei V. Tepikin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p273
RENAL AND ELECTROLYTE PHYSIOLOGY, Gerhard H. Giebisch,
Section Editor
A Current View of the Mammalian Aquaglyceroporins
Aleksandra Rojek, Jeppe Praetorius, Jørgen Frøkiaer, Søren Nielsen,
and Robert A. Fenton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p301
Molecular Physiology of the WNK Kinases
Kristopher T. Kahle, Aaron M. Ring, and Richard P. Lifton p p p p p p p p p p p p p p p p p p p p p p p p p p329
Physiological Regulation of Prostaglandins in the Kidney
Chuan-Ming Hao and Matthew D. Breyer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p357
Regulation of Renal Function by the Gastrointestinal Tract: Potential
Role of Gut-Derived Peptides and Hormones
A.R. Michell, E.S. Debnam, and R.J. Unwin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p379
RESPIRATORY PHYSIOLOGY, Richard C. Boucher, Jr., Section Editor
Regulation of Airway Mucin Gene Expression
Philip Thai, Artem Loukoianov, Shinichiro Wachi, and Reen Wu p p p p p p p p p p p p p p p p p p p p405
Structure and Function of the Cell Surface (Tethered) Mucins
Christine L. Hattrup and Sandra J. Gendler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p431
viii
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Structure and Function of the Polymeric Mucins in Airways Mucus
David J. Thornton, Karine Rousseau, and Michael A. McGuckin p p p p p p p p p p p p p p p p p p p p459
Regulated Airway Goblet Cell Mucin Secretion
C. William Davis and Burton F. Dickey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p487
SPECIAL TOPIC, OBESITY, Joel Elmquist and Jeffrey Flier, Special Topic Editors
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
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The Integrative Role of CNS Fuel-Sensing Mechanisms in Energy
Balance and Glucose Regulation
Darleen Sandoval, Daniela Cota, and Randy J. Seeley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513
Mechanisms of Leptin Action and Leptin Resistance
Martin G. Myers, Michael A. Cowley, and Heike Münzberg p p p p p p p p p p p p p p p p p p p p p p p p p537
Indexes
Cumulative Index of Contributing Authors, Volumes 66–70 p p p p p p p p p p p p p p p p p p p p p p p p557
Cumulative Index of Chapter Titles, Volumes 66–70 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p560
Errata
An online log of corrections to Annual Review of Physiology articles may be found at
http://physiol.annualreviews.org/errata.shtml
Contents
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